title: Nuclear entrapment and extracellular depletion of PCOLCE is associated with muscle degeneration in oculopharyngeal muscular dystrophy.
abstract: BACKGROUND
  Muscle fibrosis characterizes degenerated muscles in muscular dystrophies and in late onset myopathies. Fibrotic muscles often exhibit thickening of the extracellular matrix (ECM). The molecular regulation of this process is not fully understood. In oculopharyngeal muscular dystrophy (OPMD), an expansion of an alanine tract at the N-terminus of poly(A)-binding protein nuclear 1 (PABPN1) causes muscle symptoms. OPMD patient muscle degeneration initiates after midlife, while at an earlier age carriers of alanine expansion mutant PABPN1 (expPABPN1) are clinically pre-symptomatic. OPMD is characterized by fibrosis in skeletal muscles but the causative molecular mechanisms are not fully understood.
  
  
  METHODS
  We studied the molecular processes that are involved in OPMD pathology using cross-species mRNA expression profiles in muscles from patients and model systems. We identified significant dysregulation of the ECM functional group, among which the procollagen C-endopeptidase enhancer 1 gene (PCOLCE) was consistently down-regulated across species. We investigated PCOLCE subcellular localization in OPMD muscle samples and OPMD model systems to investigate any functional relevance of PCOLCE down-regulation in this disease.
  
  
  RESULTS
  We found that muscle degeneration in OPMD is associated with PCOLCE down-regulation. In addition to its known presence at the ECM, we also found PCOLCE within the nucleus of muscle cells. PCOLCE sub-cellular localization changes during myoblast cell fusion and is disrupted in cells expressing mutant expPABPN1. Our results show that PCOLCE binds to soluble PABPN1 and co-localizes with aggregated PABPN1 with a preference for the mutant protein. In muscle biopsies from OPMD patients we find that extracellular PCOLCE is depleted with its concomitant enrichment within the nuclear compartment.
  
  
  CONCLUSIONS
  PCOLCE regulates collagen processing at the ECM. Depletion of extracellular PCOLCE is associated with the expression of expPABPN1 in OPMD patient muscles. PCOLCE is also localized within the nucleus where it binds to PABPN1, suggesting that PCOLCE shuttles between the ECM and the nucleus. PCOLCE preferentially binds to expPABPN1. Nuclear-localized PCOLCE is enriched in muscle cells expressing expPABPN1. We suggest that nuclear entrapment of PCOLCE and its extracellular depletion represents a novel molecular mechanism in late-onset muscle fibrosis.
authors.affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, Einthovenweg 20, Leiden, The Netherlands. V.Raz@lumc.nl
authors.forename: Vered
authors.initials: V
authors.lastname: Raz
authors.forename: Ellen
authors.initials: E
authors.lastname: Sterrenburg
authors.forename: Samantha
authors.initials: S
authors.lastname: Routledge
authors.forename: Andrea
authors.initials: A
authors.lastname: Venema
authors.forename: Barbara M
authors.initials: BM
authors.lastname: van der Sluijs
authors.forename: Capucine
authors.initials: C
authors.lastname: Trollet
authors.forename: George
authors.initials: G
authors.lastname: Dickson
authors.forename: Baziel G M
authors.initials: BG
authors.lastname: van Engelen
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
authors.forename: Michael N
authors.initials: MN
authors.lastname: Antoniou
mesh_terms: D000367:Age Factors; D000409:Alanine / Q000235:genetics; D000818:Animals; D002466:Cell Nucleolus / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000172:deficiency*; D006023:Glycoproteins / Q000172:deficiency*; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D039141:Muscular Dystrophy, Oculopharyngeal / Q000378:metabolism / Q000473:pathology*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D039122:Poly(A)-Binding Protein I / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D009124:Muscle Proteins; C576588:PABPN1 protein, human; C491555:PCOLCE protein, human; D039122:Poly(A)-Binding Protein I; D003094:Collagen; D000409:Alanine